Estimation of Rearrangement Break Rates Across the Genome

AbstractGenomic rearrangements provide an important source of novel functions by recombining genes and motifs throughout and between genomes. However, understanding how rearrangement functions to shape genomes is hard because reconstructing rearrangements is a combinatoric problem which often has many solutions. In lieu of reconstructing the history of rearrangements, we answer the question of where rearrangements are occurring in the genome by remaining agnostic to the types of rearrangement and solving the simpler problem of estimating the rate at which double-strand breaks occur at every site in a genome. We phrase this problem in graph theoretic terms and find that it is a special case of the minimum cover problem for an interval graph. We employ and modify existing algorithms for efficiently solving this problem. We implement this method as a Python program, named BRAG, and use it to estimate the break rates in the genome of the model Ascomycete mold,Neurospora crassa. We find evidence that rearrangements are more common in the subtelomeric regions of the chromosomes, which facilitates the evolution of novel genes.

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Estimation of Rearrangement Break Rates Across the Genome

10.31219/osf.io/7gthd ◽

2018 ◽

Author(s):

Christopher Hann-Soden ◽

Ian Holmes ◽

John W. Taylor

Keyword(s):

Neurospora Crassa ◽

Interval Graph ◽

Double Strand Breaks ◽

Genomic Rearrangements ◽

Strand Breaks ◽

Minimum Cover ◽

A Genome ◽

History Of ◽

Cover Problem ◽

Special Case

Genomic rearrangements provide an important source of variation, but reconstructing the history of rearrangements often has many solutions. We answer the question of where rearrangements occur by solving the simpler problem of estimating the rate of double-strand breaks at every site in a genome. This problem is a special case of the minimum cover problem for an interval graph. We implement this method as a Python program, BRAG, and use it to estimate break rates in the genome of Neurospora crassa. We find that more frequent rearrangement in the subtelomeres facilitates the evolution of novel genes.

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Increased sensitivity of subtelomeric regions to DNA double-strand breaks in a human cancer cell line

DNA Repair ◽

10.1016/j.dnarep.2009.05.004 ◽

2009 ◽

Vol 8 (8) ◽

pp. 886-900 ◽

Cited By ~ 28

Author(s):

Oliver Zschenker ◽

Avanti Kulkarni ◽

Douglas Miller ◽

Gloria. E. Reynolds ◽

Marine Granger-Locatelli ◽

...

Keyword(s):

Cell Line ◽

Cancer Cell ◽

Human Cancer ◽

Cancer Cell Line ◽

Double Strand Breaks ◽

Human Cancer Cell ◽

Dna Double Strand Breaks ◽

Strand Breaks ◽

Increased Sensitivity ◽

Subtelomeric Regions

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Processing by MRE11 is involved in the sensitivity of subtelomeric regions to DNA double-strand breaks

Nucleic Acids Research ◽

10.1093/nar/gkv714 ◽

2015 ◽

Vol 43 (16) ◽

pp. 7911-7930 ◽

Cited By ~ 6

Author(s):

Keiko Muraki ◽

Limei Han ◽

Douglas Miller ◽

John P. Murnane

Keyword(s):

Double Strand Breaks ◽

Dna Double Strand Breaks ◽

Strand Breaks ◽

Subtelomeric Regions

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TALEN-mediated genome editing: prospects and perspectives

Biochemical Journal ◽

10.1042/bj20140295 ◽

2014 ◽

Vol 462 (1) ◽

pp. 15-24 ◽

Cited By ~ 65

Author(s):

David A. Wright ◽

Ting Li ◽

Bing Yang ◽

Martin H. Spalding

Keyword(s):

Genome Editing ◽

Double Strand Breaks ◽

Zinc Finger Nucleases ◽

Transcription Activator ◽

Strand Breaks ◽

Natural Processes ◽

Current State ◽

A Genome ◽

Dna Dsbs ◽

Repair Mechanisms

Genome editing is the practice of making predetermined and precise changes to a genome by controlling the location of DNA DSBs (double-strand breaks) and manipulating the cell's repair mechanisms. This technology results from harnessing natural processes that have taken decades and multiple lines of inquiry to understand. Through many false starts and iterative technology advances, the goal of genome editing is just now falling under the control of human hands as a routine and broadly applicable method. The present review attempts to define the technique and capture the discovery process while following its evolution from meganucleases and zinc finger nucleases to the current state of the art: TALEN (transcription-activator-like effector nuclease) technology. We also discuss factors that influence success, technical challenges and future prospects of this quickly evolving area of study and application.

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Simultaneous precise editing of multiple genes in human cells

Nucleic Acids Research ◽

10.1093/nar/gkz669 ◽

2019 ◽

Vol 47 (19) ◽

pp. e116-e116 ◽

Cited By ~ 17

Author(s):

Stephan Riesenberg ◽

Manjusha Chintalapati ◽

Dominik Macak ◽

Philipp Kanis ◽

Tomislav Maricic ◽

...

Keyword(s):

Genome Editing ◽

Kinase Inhibitor ◽

Double Strand Breaks ◽

End Joining ◽

Nucleotide Substitutions ◽

Strand Breaks ◽

Homology Directed Repair ◽

A Genome ◽

Dependent Protein ◽

Non Homologous End Joining

Abstract When double-strand breaks are introduced in a genome by CRISPR they are repaired either by non-homologous end joining (NHEJ), which often results in insertions or deletions (indels), or by homology-directed repair (HDR), which allows precise nucleotide substitutions to be introduced if a donor oligonucleotide is provided. Because NHEJ is more efficient than HDR, the frequency with which precise genome editing can be achieved is so low that simultaneous editing of more than one gene has hitherto not been possible. Here, we introduced a mutation in the human PRKDC gene that eliminates the kinase activity of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). This results in an increase in HDR irrespective of cell type and CRISPR enzyme used, sometimes allowing 87% of chromosomes in a population of cells to be precisely edited. It also allows for precise editing of up to four genes simultaneously (8 chromosomes) in the same cell. Transient inhibition of DNA-PKcs by the kinase inhibitor M3814 is similarly able to enhance precise genome editing.

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Telomere length dynamics in response to DNA damage in malaria parasites

10.1101/2020.11.08.373563 ◽

2020 ◽

Author(s):

Jake Reed ◽

Laura A Kirkman ◽

Bjӧrn FC Kafsack ◽

Christopher Mason ◽

Kirk W Deitsch

Keyword(s):

Double Strand Breaks ◽

Genome Integrity ◽

Dna Breaks ◽

Strand Breaks ◽

Host Parasite Interactions ◽

Evolutionarily Conserved ◽

Long Read ◽

Host Parasite ◽

Variant Antigen ◽

Subtelomeric Regions

SUMMARYMalaria remains a major cause of morbidity and mortality within the developing world. Recent work has implicated chromosome end stability and the repair of DNA breaks through telomere healing as potent drivers of variant antigen diversification, thus associating basic mechanisms for maintaining genome integrity with aspects of host-parasite interactions. Here we applied long-read sequencing technology to precisely examine the dynamics of telomere addition and chromosome end stabilization in response to double strand breaks within subtelomeric regions. We observed that the process of telomere healing induces the initial synthesis of telomere repeats well in excess of the minimal number required for end stability. However once stabilized, these newly created telomeres appear to function normally, eventually returning to a length nearing that of intact chromosome ends. These results parallel recent observations in humans, suggesting an evolutionarily conserved mechanism for chromosome end repair.

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Genomic Instability and Cancer Risk Associated with Erroneous DNA Repair

International Journal of Molecular Sciences ◽

10.3390/ijms222212254 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12254

Author(s):

Ken-ichi Yoshioka ◽

Rika Kusumoto-Matsuo ◽

Yusuke Matsuno ◽

Masamichi Ishiai

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cancer Risk ◽

Genomic Instability ◽

Double Strand Breaks ◽

Genomic Rearrangements ◽

Repair Pathway ◽

Dna Double Strand Breaks ◽

Brca1 And Brca2 ◽

Strand Breaks

Many cancers develop as a consequence of genomic instability, which induces genomic rearrangements and nucleotide mutations. Failure to correct DNA damage in DNA repair defective cells, such as in BRCA1 and BRCA2 mutated backgrounds, is directly associated with increased cancer risk. Genomic rearrangement is generally a consequence of erroneous repair of DNA double-strand breaks (DSBs), though paradoxically, many cancers develop in the absence of DNA repair defects. DNA repair systems are essential for cell survival, and in cancers deficient in one repair pathway, other pathways can become upregulated. In this review, we examine the current literature on genomic alterations in cancer cells and the association between these alterations and DNA repair pathway inactivation and upregulation.

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Molecular mechanisms of the formation of DNA double-strand breaks and induction of genomic rearrangements

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis ◽

10.1016/0027-5107(92)90183-3 ◽

1992 ◽

Vol 266 (2) ◽

pp. 163-170 ◽

Cited By ~ 8

Author(s):

Rudolf I. Salganik ◽

Grigory L. Dianov

Keyword(s):

Molecular Mechanisms ◽

Double Strand Breaks ◽

Genomic Rearrangements ◽

Dna Double Strand Breaks ◽

Strand Breaks

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Meiotic Crossover Patterning

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.681123 ◽

2021 ◽

Vol 9 ◽

Author(s):

Nila M. Pazhayam ◽

Carolyn A. Turcotte ◽

Jeff Sekelsky

Keyword(s):

Chromosome Segregation ◽

Chromosome Pair ◽

Double Strand Breaks ◽

Current Understanding ◽

Genetic Studies ◽

Strand Breaks ◽

Proper Number ◽

Key Players ◽

Meiotic Crossover ◽

History Of

Proper number and placement of meiotic crossovers is vital to chromosome segregation, with failures in normal crossover distribution often resulting in aneuploidy and infertility. Meiotic crossovers are formed via homologous repair of programmed double-strand breaks (DSBs). Although DSBs occur throughout the genome, crossover placement is intricately patterned, as observed first in early genetic studies by Muller and Sturtevant. Three types of patterning events have been identified. Interference, first described by Sturtevant in 1915, is a phenomenon in which crossovers on the same chromosome do not occur near one another. Assurance, initially identified by Owen in 1949, describes the phenomenon in which a minimum of one crossover is formed per chromosome pair. Suppression, first observed by Beadle in 1932, dictates that crossovers do not occur in regions surrounding the centromere and telomeres. The mechanisms behind crossover patterning remain largely unknown, and key players appear to act at all scales, from the DNA level to inter-chromosome interactions. There is also considerable overlap between the known players that drive each patterning phenomenon. In this review we discuss the history of studies of crossover patterning, developments in methods used in the field, and our current understanding of the interplay between patterning phenomena.

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